The overall goal of this project is to develop a biologic therapeutic to treat systemic inflammatory response syndrome (SIRS) using a novel human recombinant lactoferrin that contains "humanized" glycosylation patterns. SIRS is a clinical expression of the action of complex acute-phase intrinsic mediators that precedes sepsis and subsequent tissue damage leading to Multiple Organ Failure. The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. There is a great need for development of therapeutics to combat SIRS before its progression to sepsis. During sepsis, immune homeostasis is lost leading to destructive immunopathology. This proposal will examine lactoferrin's effects to mediate cellular responses during the development of bacterial-induced systemic inflammation in mice. Focus will be made on utility of rhLF, with dose range comparisons made to commercially available human milk- and neutrophil-derived lactoferrins. A battery of tests will be employed to include measurement of pro-inflammatory mediators and gene expression profiles following specific bacterial insult. The systemic events associated with lactoferrin mediation will also be investigated using methicillin-resistant Staphylococcus aureus bacteria (MRSA) infection, which is troublesome in hospital-associated (nosocomial) infections. There is a defined need to address development of therapeutics and cautionary procedures to ensure containment within the general population. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from both Gram-negative bacteria, as well as Gram-positive bacteria such as Staphylococcus aureus. PUBLIC HEALTH RELEVANCE: The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. SIRS describes the clinical manifestations derived from an acute nonspecific illness preceding septicemia, whereas an infectious etiology is required for the exact diagnosis of sepsis. There is a great need for development of therapeutics to address the early stages of insult-induced inflammation and to prevent its progression. In particular, this become an important issue with both Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which is troublesome in hospital-associated (nosocomial) infections. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from Gram-positive bacteria, such as Staphylococcus aureus, as well as from Gram-negative entities. The goal of this proposal is to examine the utility of a novel human recombinant Lactoferrin to combat SIRS, and limit progression of SIRS.